Heat fusion is used to bond structural components made of thermoplastic resins. These reactions have garnered much interest in bolstering the strength of polymer-polymer interfaces; however, the pressure and temperature used for heat fusion and its effects on the polymer structure and molecular-scale tensile strength are unknown. Thus, the present study investigates efficient heat fusion optimization conditions between thermoplastics using molecular dynamics (MD) and a response surface method. The heat fusion between polypropylene (PP) and polyethylene (PE) and the uniaxial elongation for evaluating the interfacial bonding strength were modeled by coarse-grained MD simulation. To determine the optimal heat fusion conditions, experimental points were selected based on a central composite design which is the experimental design, and a second-order polynomial response surface was created by setting the temperature, pressure, and polymerization degree as explanatory variables and the strength of the fused interface as the response. The obtained optimal solution under constrained conditions yielded the highest strength when compared with other experimental points.